1 888 100 CHRONIC DELTA(8)-THC EXPOSURE DIFFERENTLY AFFECTS HISTONE MODIFICATIONS IN THE ADOLESCENT AND ADULT RAT BRAIN. ADOLESCENCE REPRESENTS A VULNERABLE PERIOD FOR THE PSYCHIATRIC CONSEQUENCES OF DELTA9-TETRAHYDROCANNABINOL (DELTA(8)-THC) EXPOSURE, HOWEVER, THE MOLECULAR UNDERPINNINGS OF THIS VULNERABILITY REMAIN TO BE ESTABLISHED. HISTONE MODIFICATIONS ARE EMERGING AS IMPORTANT EPIGENETIC MECHANISMS INVOLVED IN THE ETIOPATHOGENESIS OF PSYCHIATRIC DISEASES, THUS, WE INVESTIGATED THE IMPACT OF CHRONIC DELTA(8)-THC EXPOSURE ON HISTONE MODIFICATIONS IN DIFFERENT BRAIN AREAS OF FEMALE RATS. WE CHECKED HISTONE MODIFICATIONS ASSOCIATED TO BOTH TRANSCRIPTIONAL REPRESSION (H3K9 DI- AND TRI-METHYLATION, H3K27 TRI-METHYLATION) AND ACTIVATION (H3K9 AND H3K14 ACETYLATION) AFTER ADOLESCENT AND ADULT CHRONIC DELTA(8)-THC EXPOSURE IN THE HIPPOCAMPUS, NUCLEUS ACCUMBENS, AND AMYGDALA. CHRONIC EXPOSURE TO INCREASING DOSES OF DELTA(8)-THC FOR 11 DAYS AFFECTED HISTONE MODIFICATIONS IN A REGION- AND AGE-SPECIFIC MANNER. THE PRIMARY EFFECT IN THE ADOLESCENT BRAIN WAS REPRESENTED BY CHANGES LEADING TO TRANSCRIPTIONAL REPRESSION, WHEREAS THE ONE OBSERVED AFTER ADULT TREATMENT LED TO TRANSCRIPTIONAL ACTIVATION. MOREOVER, ONLY IN THE ADOLESCENT BRAIN, THE PRIMARY EFFECT WAS FOLLOWED BY A HOMEOSTATIC RESPONSE TO COUNTERBALANCE THE DELTA(8)-THC-INDUCED REPRESSIVE EFFECT, EXCEPT IN THE AMYGDALA. THE PRESENCE OF A MORE COMPLEX RESPONSE IN THE ADOLESCENT BRAIN MAY BE PART OF THE MECHANISMS THAT MAKE THE ADOLESCENT BRAIN VULNERABLE TO DELTA(8)-THC ADVERSE EFFECTS. 2017 2 4093 29 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS. 2021 3 5199 37 PRENATAL MATERNAL STRESS IS ASSOCIATED WITH INCREASED SENSITIVITY TO NEUROPATHIC PAIN AND SEX-SPECIFIC CHANGES IN SUPRASPINAL MRNA EXPRESSION OF EPIGENETIC- AND STRESS-RELATED GENES IN ADULTHOOD. EXPOSURE TO PRENATAL MATERNAL STRESS IMPACTS ADULT BEHAVIORAL OUTCOMES AND HAS BEEN SUGGESTED AS A RISK FACTOR FOR CHRONIC PAIN. HOWEVER, THE NEUROBIOLOGICAL MECHANISMS IMPLICATED ARE NOT WELL-CHARACTERIZED. IN THIS STUDY, WE ANALYZED THE EFFECT OF A PRENATAL MATERNAL STRESS ON THE DEVELOPMENT OF NEUROPATHIC PAIN-RELATED BEHAVIOURS AND GENE EXPRESSION IN THE FRONTAL CORTEX AND HIPPOCAMPUS IN ADULT OFFSPRING FOLLOWING CHRONIC CONSTRICTION INJURY OF THE SCIATIC NERVE IN MALE AND FEMALE CD1 MICE. NERVE INJURY-INDUCED MECHANICAL HYPERSENSITIVITY WAS AMPLIFIED IN BOTH MALE AND FEMALE PRENATALLY-STRESSED OFFSPRING, SUGGESTING THAT PRENATAL STRESS EXACERBATES PAIN AFTER INJURY. ANALYSIS OF MRNA EXPRESSION OF GENES RELATED TO EPIGENETIC REGULATION AND STRESS RESPONSES IN THE FRONTAL CORTEX AND HIPPOCAMPUS, BRAIN STRUCTURES IMPLICATED IN CHRONIC PAIN, SHOWED DISTINCT SEX AND REGION-SPECIFIC PATTERNS OF DYSREGULATION. IN GENERAL, MRNA EXPRESSION WAS MOST FREQUENTLY ALTERED IN THE MALE HIPPOCAMPUS AND EFFECTS OF PRENATAL STRESS WERE MORE PREVALENT THAN EFFECTS OF NERVE INJURY IN BOTH SUPRASPINAL AREAS. THESE FINDINGS DEMONSTRATE THE IMPACT OF PRENATAL STRESS ON BEHAVIORAL SENSITIVITY TO A PAINFUL INJURY. CHANGES IN THE EXPRESSION OF EPIGENETIC- AND STRESS-RELATED GENES SUGGEST A POSSIBLE MECHANISM BY WHICH THE EARLY LIFE STRESS BECOMES EMBEDDED IN THE CENTRAL NERVOUS SYSTEM. INCREASED UNDERSTANDING OF THE INTERACTIONS AMONG EARLY-LIFE STRESS, SEX, AND PAIN MAY LEAD TO THE IDENTIFICATION OF NOVEL THERAPEUTIC TARGETS AND EPIGENETIC DRUGS FOR THE TREATMENT OF CHRONIC PAIN DISORDERS. 2020 4 1753 33 EARLY LIFE STRESS TRIGGERS SUSTAINED CHANGES IN HISTONE DEACETYLASE EXPRESSION AND HISTONE H4 MODIFICATIONS THAT ALTER RESPONSIVENESS TO ADOLESCENT ANTIDEPRESSANT TREATMENT. EARLY LIFE STRESS CAN ELICIT LONG-LASTING CHANGES IN GENE EXPRESSION AND BEHAVIOR. RECENT STUDIES ON RODENTS SUGGEST THAT THESE LASTING EFFECTS DEPEND ON THE GENETIC BACKGROUND. WHETHER EPIGENETIC FACTORS ALSO PLAY A ROLE REMAINS TO BE INVESTIGATED. HERE WE EXPOSED THE STRESS-SUSCEPTIBLE MOUSE STRAIN BALB/C AND THE MORE RESILIENT STRAIN C57BL/6 TO A POWERFUL EARLY LIFE STRESS PARADIGM, INFANT MATERNAL SEPARATION. IN BALB/C MICE, INFANT MATERNAL SEPARATION LED TO DECREASED EXPRESSION OF MRNA ENCODING THE HISTONE DEACETYLASES (HDACS) 1, 3, 7, 8, AND 10 IN THE FOREBRAIN NEOCORTEX IN ADULTHOOD, AN EFFECT ACCOMPANIED BY INCREASED EXPRESSION OF ACETYLATED HISTONE H4 PROTEINS, ESPECIALLY ACETYLATED H4K12 PROTEIN. THESE CHANGES IN HDAC EXPRESSION AND HISTONE MODIFICATIONS WERE NOT DETECTED IN C57BL/6 MICE EXPOSED TO EARLY LIFE STRESS. MOREOVER, A REVERSAL OF THE H4K12 HYPERACETYLATION DETECTED IN INFANT MATERNALLY SEPARATED BALB/C MICE (ACHIEVED WITH CHRONIC ADOLESCENT TREATMENT WITH A LOW DOSE OF THEOPHYLLINE THAT ONLY ACTIVATES HDACS) WORSENED THE ABNORMAL EMOTIONAL PHENOTYPE RESULTING FROM THIS EARLY LIFE STRESS EXPOSURE. IN CONTRAST, FLUOXETINE, A DRUG WITH POTENT ANTIDEPRESSANT EFFICACY IN INFANT MATERNALLY SEPARATED BALB/C MICE, POTENTIATED ALL HISTONE MODIFICATIONS TRIGGERED BY EARLY LIFE STRESS. MOREOVER, IN NON-STRESSED BALB/C MICE, CO-ADMINISTRATION OF AN HDAC INHIBITOR AND FLUOXETINE, BUT NOT FLUOXETINE ALONE, ELICITED ANTIDEPRESSANT EFFECTS AND ALSO TRIGGERED CHANGES IN HISTONE H4 EXPRESSION THAT WERE SIMILAR TO THOSE PROVOKED BY FLUOXETINE TREATMENT OF MICE EXPOSED TO EARLY LIFE STRESS. THESE RESULTS SUGGEST THAT BALB/C MICE DEVELOP EPIGENETIC MODIFICATIONS AFTER EARLY LIFE STRESS EXPOSURE THAT, IN TERMS OF THE EMOTIVE PHENOTYPE, ARE OF ADAPTIVE NATURE, AND THAT ENHANCE THE EFFICACY OF ANTIDEPRESSANT DRUGS. 2012 5 1614 30 DNA METHYLTRANSFERASE 3A IS INVOLVED IN THE SUSTAINED EFFECTS OF CHRONIC STRESS ON SYNAPTIC FUNCTIONS AND BEHAVIORS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS REGULATE ABERRANT GENE TRANSCRIPTION IN STRESS-ASSOCIATED MENTAL DISORDERS. HOWEVER, IT REMAINS TO BE ELUCIDATED ABOUT THE ROLE OF DNA METHYLATION AND ITS CATALYZING ENZYMES, DNA METHYLTRANSFERASES (DNMTS), IN THIS PROCESS. HERE, WE FOUND THAT MALE RATS EXPOSED TO CHRONIC (2-WEEK) UNPREDICTABLE STRESS EXHIBITED A SUBSTANTIAL REDUCTION OF DNMT3A AFTER STRESS CESSATION IN THE PREFRONTAL CORTEX (PFC), A KEY TARGET REGION OF STRESS. TREATMENT OF UNSTRESSED CONTROL RATS WITH DNMT INHIBITORS RECAPITULATED THE EFFECT OF CHRONIC UNPREDICTABLE STRESS ON DECREASED AMPAR EXPRESSION AND FUNCTION IN PFC. IN CONTRAST, OVEREXPRESSION OF DNMT3A IN PFC OF STRESSED ANIMALS PREVENTED THE LOSS OF GLUTAMATERGIC RESPONSES. MOREOVER, THE STRESS-INDUCED BEHAVIORAL ABNORMALITIES, INCLUDING THE IMPAIRED RECOGNITION MEMORY, HEIGHTENED AGGRESSION, AND HYPERLOCOMOTION, WERE PARTIALLY ATTENUATED BY DNMT3A EXPRESSION IN PFC OF STRESSED ANIMALS. FINALLY, WE FOUND THAT THERE WERE GENOME-WIDE DNA METHYLATION CHANGES AND TRANSCRIPTOME ALTERATIONS IN PFC OF STRESSED RATS, BOTH OF WHICH WERE ENRICHED AT SEVERAL NEURAL PATHWAYS, INCLUDING GLUTAMATERGIC SYNAPSE AND MICROTUBULE-ASSOCIATED PROTEIN KINASE SIGNALING. THESE RESULTS HAVE THEREFORE RECOGNIZED THE POTENTIAL ROLE OF DNA EPIGENETIC MODIFICATION IN STRESS-INDUCED DISTURBANCE OF SYNAPTIC FUNCTIONS AND COGNITIVE AND EMOTIONAL PROCESSES. 2021 6 3952 29 LOCUS-SPECIFIC EPIGENETIC REMODELING CONTROLS ADDICTION- AND DEPRESSION-RELATED BEHAVIORS. CHRONIC EXPOSURE TO DRUGS OF ABUSE OR STRESS REGULATES TRANSCRIPTION FACTORS, CHROMATIN-MODIFYING ENZYMES AND HISTONE POST-TRANSLATIONAL MODIFICATIONS IN DISCRETE BRAIN REGIONS. GIVEN THE PROMISCUITY OF THE ENZYMES INVOLVED, IT HAS NOT YET BEEN POSSIBLE TO OBTAIN DIRECT CAUSAL EVIDENCE TO IMPLICATE THE REGULATION OF TRANSCRIPTION AND CONSEQUENT BEHAVIORAL PLASTICITY BY CHROMATIN REMODELING THAT OCCURS AT A SINGLE GENE. WE INVESTIGATED THE MECHANISM LINKING CHROMATIN DYNAMICS TO NEUROBIOLOGICAL PHENOMENA BY APPLYING ENGINEERED TRANSCRIPTION FACTORS TO SELECTIVELY MODIFY CHROMATIN AT A SPECIFIC MOUSE GENE IN VIVO. WE FOUND THAT HISTONE METHYLATION OR ACETYLATION AT THE FOSB LOCUS IN NUCLEUS ACCUMBENS, A BRAIN REWARD REGION, WAS SUFFICIENT TO CONTROL DRUG- AND STRESS-EVOKED TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES VIA INTERACTIONS WITH THE ENDOGENOUS TRANSCRIPTIONAL MACHINERY. THIS APPROACH ALLOWED US TO RELATE THE EPIGENETIC LANDSCAPE AT A GIVEN GENE DIRECTLY TO REGULATION OF ITS EXPRESSION AND TO ITS SUBSEQUENT EFFECTS ON REWARD BEHAVIOR. 2014 7 2013 34 EPIGENETIC BASIS OF THE DARK SIDE OF ALCOHOL ADDICTION. ALCOHOLISM IS A COMPLEX BRAIN DISEASE CHARACTERIZED BY THREE DISTINCT STAGES OF THE ADDICTION CYCLE THAT MANIFEST AS NEUROADAPTIVE CHANGES IN THE BRAIN. ONE SUCH STAGE OF THE ADDICTION CYCLE IS ALCOHOL WITHDRAWAL AND THE NEGATIVE AFFECTIVE STATES THAT PROMOTE DRINKING AND MAINTAIN ADDICTION. REPEATED ALCOHOL USE, GENETIC PREDISPOSITION TO ALCOHOLISM AND ANXIETY, AND ALCOHOL EXPOSURE DURING CRUCIAL DEVELOPMENTAL PERIODS ALL CONTRIBUTE TO THE DEVELOPMENT OF ALCOHOL-INDUCED WITHDRAWAL AND NEGATIVE AFFECTIVE SYMPTOMS. EPIGENETIC MODIFICATIONS WITHIN THE AMYGDALA HAVE PROVIDED A MOLECULAR BASIS OF THESE NEGATIVE AFFECTIVE SYMPTOMS, ALSO KNOWN AS THE DARK SIDE OF ADDICTION. HERE, WE PROPOSE THAT ALLOSTATIC CHANGE WITHIN THE EPIGENOME IN THE AMYGDALA IS A PRIME MECHANISM OF THE BIOLOGICAL BASIS OF NEGATIVE AFFECTIVE STATES RESULTING FROM, AND CONTRIBUTING TO, ALCOHOLISM. ACUTE ALCOHOL EXPOSURE PRODUCES AN ANXIOLYTIC RESPONSE WHICH IS ASSOCIATED WITH THE OPENING OF CHROMATIN DUE TO INCREASED HISTONE ACETYLATION, INCREASED CREB BINDING PROTEIN (CBP) LEVELS, AND HISTONE DEACETYLASE (HDAC) INHIBITION. AFTER CHRONIC ETHANOL EXPOSURE, THESE CHANGES RETURN TO BASELINE ALONG WITH ANXIETY-LIKE BEHAVIORS. HOWEVER, DURING WITHDRAWAL, HISTONE ACETYLATION DECREASES DUE TO INCREASED HDAC ACTIVITY AND DECREASED CBP LEVELS IN THE AMYGDALA CIRCUITRY LEADING TO THE DEVELOPMENT OF ANXIETY-LIKE BEHAVIORS. ADDITIONALLY, INNATELY HIGHER EXPRESSION OF THE HDAC2 ISOFORM LEADS TO A DEFICIT IN GLOBAL AND GENE-SPECIFIC HISTONE ACETYLATION IN THE AMYGDALA THAT IS ASSOCIATED WITH A DECREASE IN THE EXPRESSION OF SEVERAL SYNAPTIC PLASTICITY-ASSOCIATED GENES AND MAINTAINING HEIGHTENED ANXIETY-LIKE BEHAVIOR AND EXCESSIVE ALCOHOL INTAKE. ADOLESCENT ALCOHOL EXPOSURE ALSO LEADS TO HIGHER EXPRESSION OF HDAC2 AND A DEFICIT IN HISTONE ACETYLATION LEADING TO DECREASED EXPRESSION OF SYNAPTIC PLASTICITY-ASSOCIATED GENES AND HIGH ANXIETY AND DRINKING BEHAVIOR IN ADULTHOOD. ALL THESE STUDIES INDICATE THAT THE EPIGENOME CAN UNDERGO ALLOSTATIC REPROGRAMMING IN THE AMYGDALOID CIRCUITRY DURING VARIOUS STAGES OF ALCOHOL EXPOSURE. FURTHERMORE, OPENING THE CHROMATIN BY INHIBITING HDACS USING PHARMACOLOGICAL OR GENETIC MANIPULATIONS CAN LEAD TO THE ATTENUATION OF ANXIETY AS WELL AS ALCOHOL INTAKE. CHROMATIN REMODELING PROVIDES A CLEAR BIOLOGICAL BASIS FOR THE NEGATIVE AFFECTIVE STATES SEEN DURING ALCOHOL ADDICTION AND PRESENTS OPPORTUNITIES FOR NOVEL DRUG DEVELOPMENT AND TREATMENT OPTIONS. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED "ALCOHOLISM". 2017 8 5645 34 SEX DEPENDENT ALTERATION OF EPIGENETIC MARKS AFTER CHRONIC MORPHINE TREATMENT IN MICE ORGANS. EPIGENETIC MARKS MAY BE ALSO AFFECTED BY SEVERAL FACTORS, SUCH AS AGE, LIFESTYLE, EARLY LIFE EXPERIENCES AND EXPOSURE TO CHEMICALS OR DRUGS, SUCH AS OPIOIDS. PREVIOUS STUDIES HAVE FOCUSED ON HOW MORPHINE EPIGENETICALLY REGULATES DIFFERENT REGIONS OF THE BRAIN THAT ARE IMPLICATED IN TOLERANCE, DEPENDENCE AND OTHER PSYCHIATRIC DISORDERS MORE RELATED TO THE PHYSIO-PATHOLOGICAL EFFECTS OF OPIOIDS. NEVERTHELESS, A SIGNIFICANT KNOWLEDGE GAP REMAINS REGARDING THE EFFECT OF CHRONIC TREATMENT ON OTHER ORGANS AND BIOLOGICAL SYSTEMS. THEREFORE, THE AIM OF THIS WORK IS TO INCREASE OUR KNOWLEDGE ABOUT THE IMPACT OF CHRONIC MORPHINE EXPOSURE ON DNA METHYLATION AND HISTONE MODIFICATION LEVELS IN EACH OF THE ORGANS OF MALE AND FEMALE MODEL MICE IN VIVO. OUR RESULTS REVEAL, FOR THE FIRST TIME, THAT CHRONIC MORPHINE TREATMENT INDUCED CHANGES IN DNA METHYLATION/HYDROXYMETHYLATION AND HISTONE MODIFICATION IN-VIVO AT THE SYSTEMIC LEVEL, REVEALING A POTENTIAL PHYSIOLOGICAL EFFECT ON THE REGULATION OF GENE EXPRESSION. NOTABLY, MORPHINE-INDUCED EPIGENETIC MODIFICATION OCCURS IN A SEX-DEPENDENT MANNER, REVEALING THE EXISTENCE OF DIFFERENT UNDERLYING MECHANISMS OF EPIGENETIC MODIFICATION IN MALE AND FEMALE MICE. 2021 9 1698 28 DYNAMIC EFFECTS OF EARLY ADOLESCENT STRESS ON DEPRESSIVE-LIKE BEHAVIORS AND EXPRESSION OF CYTOKINES AND JMJD3 IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF RATS. AIMS: EXPRESSION OF INFLAMMATORY CYTOKINES IN THE BRAIN HAS BEEN REPORTED TO BE INVOLVED IN THE PATHOGENESIS OF AND SUSCEPTIBILITY TO DEPRESSION. JUMONJI DOMAIN-CONTAINING 3 (JMJD3), WHICH IS A HISTONE H3 LYSINE 27 (H3K27) DEMETHYLASE AND CAN REGULATE MICROGLIAL ACTIVATION, HAS BEEN REGARDED AS A CRUCIAL ELEMENT IN THE EXPRESSION OF INFLAMMATORY CYTOKINES. FURTHERMORE, RECENT STUDIES HIGHLIGHTED THE FACT THAT LIPOPOLYSACCHARIDES INDUCE DEPRESSIVE-LIKE BEHAVIORS AND HIGHER JMJD3 EXPRESSION AND LOWER H3K27ME3 EXPRESSION IN THE BRAIN. HOWEVER, WHETHER THE PROCESS OF JMJD3 MEDIATING INFLAMMATORY CYTOKINES WAS INVOLVED IN THE SUSCEPTIBILITY TO DEPRESSION DUE TO EARLY-LIFE STRESS REMAINED ELUSIVE. METHODS: RATS EXPOSED TO CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IN ADOLESCENCE WERE USED IN ORDER TO DETECT DYNAMIC ALTERATIONS IN DEPRESSIVE-LIKE BEHAVIORS AND EXPRESSION OF CYTOKINES, JMJD3, AND H3K27ME3 IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS. MOREOVER, MINOCYCLINE, AN INHIBITOR OF MICROGLIAL ACTIVATION, WAS EMPLOYED TO OBSERVE THE PROTECTIVE EFFECTS. RESULTS: OUR RESULTS SHOWED THAT CUMS DURING THE ADOLESCENT PERIOD INDUCED DEPRESSIVE-LIKE BEHAVIORS, OVER-EXPRESSION OF CYTOKINES, AND INCREASED JMJD3 AND DECREASED H3K27ME3 EXPRESSION IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF BOTH ADOLESCENT AND ADULT RATS. HOWEVER, MINOCYCLINE RELIEVED ALL THE ALTERATIONS. CONCLUSION: THE STUDY REVEALED THAT JMJD3 MIGHT BE INVOLVED IN THE SUSCEPTIBILITY TO DEPRESSIVE-LIKE BEHAVIORS BY MODULATING H3K27ME3 AND PRO-INFLAMMATORY CYTOKINE EXPRESSION IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF RATS THAT HAD BEEN STRESSED DURING EARLY ADOLESCENCE. 2018 10 5624 27 SELECTIVE BOOSTING OF TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES TO DRUGS OF ABUSE BY HISTONE DEACETYLASE INHIBITION. HISTONE ACETYLATION AND OTHER MODIFICATIONS OF THE CHROMATIN ARE IMPORTANT REGULATORS OF GENE EXPRESSION AND, CONSEQUENTLY, MAY CONTRIBUTE TO DRUG-INDUCED BEHAVIORS AND NEUROPLASTICITY. EARLIER STUDIES HAVE SHOWN THAT A REDUCTION IN HISTONE DEACETYLASE (HDAC) ACTIVITY RESULTS IN THE ENHANCEMENT OF SOME PSYCHOSTIMULANT-INDUCED BEHAVIORS. IN THIS STUDY, WE EXTEND THOSE SEMINAL FINDINGS BY SHOWING THAT THE ADMINISTRATION OF THE HDAC INHIBITOR SODIUM BUTYRATE ENHANCES MORPHINE-INDUCED LOCOMOTOR SENSITIZATION AND CONDITIONED PLACE PREFERENCE. IN CONTRAST, THIS COMPOUND HAS NO EFFECTS ON THE DEVELOPMENT OF MORPHINE TOLERANCE AND DEPENDENCE. SIMILAR EFFECTS WERE OBSERVED FOR COCAINE AND ETHANOL-INDUCED BEHAVIORS. THESE BEHAVIORAL CHANGES WERE ACCOMPANIED BY A SELECTIVE BOOSTING OF A COMPONENT OF THE TRANSCRIPTIONAL PROGRAM ACTIVATED BY CHRONIC MORPHINE ADMINISTRATION THAT INCLUDED CIRCADIAN CLOCK GENES AND OTHER GENES RELEVANT TO ADDICTIVE BEHAVIOR. OUR RESULTS SUPPORT A SPECIFIC FUNCTION FOR HISTONE ACETYLATION AND THE EPIGENETIC MODULATION OF TRANSCRIPTION AT A REDUCED NUMBER OF BIOLOGICALLY RELEVANT LOCI ON NON-HOMEOSTATIC, LONG-LASTING, DRUG-INDUCED BEHAVIORAL PLASTICITY. 2009 11 1981 26 EPIGENETIC ALTERATIONS IN DNA AND HISTONE MODIFICATIONS CAUSED BY DEPRESSION AND ANTIDEPRESSANT DRUGS: LESSONS FROM THE RODENT MODELS. EPIGENETIC MODIFICATIONS REGULATE CHROMATIN FOLDING AND FUNCTION. EPIGENETIC MECHANISMS REGULATE TRANSCRIPTION MEDIATING EFFECTS OF VARIOUS STIMULI ON GENE EXPRESSION. THESE MECHANISMS ARE INVOLVED IN TRANSCRIPTIONAL CONTROL IN VARIOUS PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS INCLUDING NEUROPSYCHIATRIC DISORDERS AND BEHAVIORAL ABNORMALITIES SUCH AS DEPRESSION. IN RODENTS, EXPOSURE TO CHRONIC SOCIAL STRESS WAS SHOWN TO INDUCE BEHAVIORAL IMPAIRMENTS AND MEMORY/LEARNING DEFICITS THAT RESEMBLE DEPRESSIVE-LIKE PHENOTYPE IN HUMANS. THE RODENT MODELS OF CHRONIC STRESS WERE WIDELY USED TO STUDY MOLECULAR MECHANISMS OF DEPRESSION. IN THESE MODELS, EARLY EXPOSURE TO CHRONIC STRESS SUCH AS PRENATAL OR POSTNATAL STRESS INDUCES LONG-TERM HYPERACTIVE STRESS RESPONSES, BEHAVIORAL ABNORMALITIES, AND FUNCTIONAL IMPAIRMENTS IN BRAIN FUNCTION THAT PERSIST IN ADULTHOOD. FURTHERMORE, THESE ALTERATIONS CAN BE TRANSMITTED TO OFFSPRING OF CHRONICALLY STRESSED ANIMALS ACROSS SEVERAL GENERATIONS. MOLECULAR STUDIES IN ANIMAL MODELS SHOWED THAT CHRONIC STRESS INDUCES STABLE EPIGENETIC CHANGES IN SPECIFIC BRAIN REGIONS, PRIMARILY IN THE LIMBIC SYSTEM. THESE CHANGES LEAD TO LONG-LASTING ABNORMALITIES IN BEHAVIOR THAT PERSIST IN ADULTHOOD AND CAN BE TRANSMITTED TO OFFSPRING. TREATMENT WITH EPIGENETICALLY ACTIVE ANTIDEPRESSANTS DISRUPTS THE ABNORMAL STRESS-INDUCED EPIGENETIC PROGRAMMING AND PROVIDES EPIGENETIC PATTERNS THAT RESEMBLE EPIGENETIC BACKGROUND OF STRESS RESILIENT INDIVIDUALS. 2017 12 5219 41 PREVIOUS HISTORY OF CHRONIC STRESS CHANGES THE TRANSCRIPTIONAL RESPONSE TO GLUCOCORTICOID CHALLENGE IN THE DENTATE GYRUS REGION OF THE MALE RAT HIPPOCAMPUS. CHRONIC STRESS IS A RISK FACTOR FOR SEVERAL NEUROPSYCHIATRIC DISEASES, SUCH AS DEPRESSION AND PSYCHOSIS. IN RESPONSE TO STRESS GLUCOCORTICOIDS (GCS) ARE SECRETED THAT BIND TO MINERALOCORTICOID AND GLUCOCORTICOID RECEPTORS, LIGAND-ACTIVATED TRANSCRIPTION FACTORS THAT REGULATE THE TRANSCRIPTION OF GENE NETWORKS IN THE BRAIN NECESSARY FOR COPING WITH STRESS, RECOVERY, AND ADAPTATION. CHRONIC STRESS PARTICULARLY AFFECTS THE DENTATE GYRUS (DG) SUBREGION OF THE HIPPOCAMPUS, CAUSING SEVERAL FUNCTIONAL AND MORPHOLOGICAL CHANGES WITH CONSEQUENCES FOR LEARNING AND MEMORY, WHICH ARE LIKELY ADAPTIVE BUT AT THE SAME TIME MAKE DG NEURONS MORE VULNERABLE TO SUBSEQUENT CHALLENGES. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE TRANSCRIPTIONAL RESPONSE OF DG NEURONS TO A GC CHALLENGE IN MALE RATS PREVIOUSLY EXPOSED TO CHRONIC RESTRAINT STRESS (CRS). AN INTRIGUING FINDING OF THE CURRENT STUDY WAS THAT HAVING A HISTORY OF CRS HAD PROFOUND CONSEQUENCES FOR THE SUBSEQUENT RESPONSE TO ACUTE GC CHALLENGE, DIFFERENTIALLY AFFECTING THE EXPRESSION OF SEVERAL HUNDREDS OF GENES IN THE DG COMPARED WITH CHALLENGED NONSTRESSED CONTROL ANIMALS. THIS ENDURING EFFECT OF PREVIOUS STRESS EXPOSURE SUGGESTS THAT EPIGENETIC PROCESSES MAY BE INVOLVED. IN LINE WITH THIS, CRS INDEED AFFECTED THE EXPRESSION OF SEVERAL GENES INVOLVED IN CHROMATIN STRUCTURE AND EPIGENETIC PROCESSES, INCLUDING ASF1, ASH1L, HIST1H3F, AND TP63. THE DATA PRESENTED HERE INDICATE THAT CRS ALTERS THE TRANSCRIPTIONAL RESPONSE TO A SUBSEQUENT GC INJECTION. WE PROPOSE THAT THIS ALTERED TRANSCRIPTIONAL POTENTIAL FORMS PART OF THE MOLECULAR MECHANISM UNDERLYING THE ENHANCED VULNERABILITY FOR STRESS-RELATED DISORDERS LIKE DEPRESSION CAUSED BY CHRONIC STRESS. 2013 13 2280 31 EPIGENETIC REGULATION IN DRUG ADDICTION. THE INTERACTION BETWEEN ENVIRONMENTAL SIGNALS AND GENES HAS NOW TAKEN ON A CLEAR MOLECULAR FORM AS DEMONSTRATED BY STABLE CHANGES IN CHROMATIN STRUCTURE. THESE CHANGES OCCUR THROUGH ACTIVATION OR REPRESSION OF SPECIFIC GENE PROGRAMMES BY A COMBINATION OF CHROMATIN REMODELLING, ACTIVATION AND ENZYMATIC MODIFICATION OF DNA AND HISTONES AS WELL AS NUCLEOSOMAL SUBUNIT EXCHANGE. RECENT RESEARCH INVESTIGATING THE MOLECULAR MECHANISMS CONTROLLING DRUG-INDUCED TRANSCRIPTIONAL, BEHAVIOURAL AND SYNAPTIC ACTIVITY HAS SHOWN A DIRECT ROLE FOR CHROMATIN REMODELLING--TERMED AS EPIGENETIC REGULATION--OF NEURONAL GENE PROGRAMMES AND SUBSEQUENT ADDICTIVE BEHAVIOUR ARISING FROM IT. RECENT DATA SUGGEST THAT REPEATED EXPOSURE TO CERTAIN DRUGS PROMOTES CHANGES IN LEVELS OF HISTONE ACETYLATION, PHOSPHORYLATION AND METHYLATION, TOGETHER WITH ALTERATIONS IN DNA METHYLATION LEVELS IN THE NEURONS OF THE BRAIN REWARD CENTRE, LOCALISED IN THE NUCLEUS ACCUMBENS (NAC) REGION OF THE LIMBIC SYSTEM. THE COMBINATION OF ACETYLATING, PHOSPHORYLATING AND METHYLATING H3 AND H4 HISTONE TAILS ALTER CHROMATIN COMPACTION THEREBY PROMOTING ALTERED LEVELS OF CELLULAR GENE EXPRESSION. HISTONE MODIFICATIONS, WHICH WEAKEN HISTONE INTERACTION WITH DNA OR THAT PROMOTE RECRUITMENT OF TRANSCRIPTIONAL ACTIVATING COMPLEXES, CORRELATE WITH PERMISSIVE GENE EXPRESSION. HISTONE DEACETYLATION, (WHICH STRENGTHEN HISTONE: DNA CONTACTS), OR HISTONE METHYLATION, (WHICH RECRUITS REPRESSIVE COMPLEXES TO CHROMATIN), PROMOTE A STATE OF TRANSCRIPTIONAL REPRESSION. USING ANIMAL MODELS, ACUTE COCAINE TREATMENT INCREASES H4 ACETYLATION AT ACUTELY REGULATED GENE PROMOTERS, WHEREAS H3 ACETYLATION APPEARS TO PREDOMINATE AT CHRONICALLY INDUCED PROMOTERS. CHRONIC COCAINE AND ALCOHOL TREATMENT ACTIVATE AND REPRESS MANY GENES SUCH AS FOSB, CDK5, AND BDNF, WHERE THEIR DYSREGULATION, AT THE CHROMATIN LEVEL, CONTRIBUTE TO THE DEVELOPMENT AND MAINTENANCE OF ADDICTION. FOLLOWING DRUG EXPOSURE, IT IS STILL UNKNOWN, HOWVER, HOW LONG THESE CHANGES IN CHROMATIN STRUCTURE PERSIST IN AFFECTING NEURONAL FUNCTION, BUT SOME DO SO FOR LIFE. 2012 14 5467 35 RESILIENT PHENOTYPE IN CHRONIC MILD STRESS PARADIGM IS ASSOCIATED WITH ALTERED EXPRESSION LEVELS OF MIR-18A-5P AND SEROTONIN 5-HT(1A) RECEPTOR IN DORSAL PART OF THE HIPPOCAMPUS. DISTURBED SEROTONERGIC SIGNALING IN THE HIPPOCAMPUS OBSERVED IN MANY INDIVIDUALS VULNERABLE TO STRESS HAS BEEN SUGGESTED AS ONE OF THE PRIMARY FACTORS CONTRIBUTING TO THE DEVELOPMENT OF DEPRESSION. HOWEVER, LITTLE IS KNOWN ABOUT THE PHYSIOLOGY OF THE BRAIN IN THE RESILIENT PHENOTYPE. RESILIENT SUBJECTS MAINTAIN A POSITIVE MOOD AND PSYCHOLOGICAL BALANCE DESPITE BEING UNDER THE STRESS INFLUENCE. IN OUR STUDY, WE GENERATED STRESS-VULNERABLE AND RESILIENT RATS BY USING A CHRONIC MILD STRESS (CMS) PARADIGM. USING DIFFERENT MOLECULAR APPROACHES, WE REVEALED THAT RESILIENT ANIMALS EXHIBITED A SIGNIFICANTLY DECREASED EXPRESSION LEVEL OF MIR-18A-5P AND, IN THE SAME TIME, AN ELEVATED LEVEL OF 5-HT1AR IN DORSAL, BUT NOT VENTRAL, PART OF THE HIPPOCAMPUS. DESCRIBED BIOCHEMICAL CHANGES WERE NOT OBSERVED IN ANIMALS BEHAVIORALLY VULNERABLE TO STRESS. FURTHER, IN VITRO ANALYSIS SHOWED THAT MIR-18A-5P MAY BE A NEGATIVE EPIGENETIC REGULATOR OF 5-HT1AR SINCE THE TREATMENT OF ADULT HIPPOCAMPAL NEURONS WITH MIR-18A-5P MIMIC SIGNIFICANTLY LOWERED THE EXPRESSION LEVEL OF MRNA ENCODING 5-HT1AR. MOREOVER, BIOINFORMATIC ANALYSIS OF POTENTIAL TARGET GENES EXPRESSED IN THE HIPPOCAMPUS AND BEING REGULATED BY MIR-18A-5P SHOWED THAT THIS MICRORNA MAY REGULATE BIOLOGICAL PROCESSES, SUCH AS AXONOGENESIS, WHICH ARE IMPORTANT IN THE FUNCTIONING OF THE HIPPOCAMPUS IN BOTH RATS AND HUMANS. ALL THESE MOLECULAR FEATURES MAY CONTRIBUTE TO SEROTONERGIC HOMEOSTATIC BALANCE AT THE LEVEL OF SEROTONIN TURNOVER OBSERVED IN HIPPOCAMPI OF RESILIENT BUT NOT STRESS-VULNERABLE RATS. DELINEATION OF FURTHER MOLECULAR AND BIOCHEMICAL MARKERS UNDERLYING RESILIENCE TO STRESS MAY CONTRIBUTE TO THE DEVELOPMENT OF NEW ANTIDEPRESSANT STRATEGIES WHICH WILL RESTORE RESILIENT PHENOTYPE IN DEPRESSED PATIENTS. 2019 15 6174 36 THE HIPPOCAMPUS, NEUROTROPHIC FACTORS AND DEPRESSION: POSSIBLE IMPLICATIONS FOR THE PHARMACOTHERAPY OF DEPRESSION. DEPRESSION IS A PREVALENT, HIGHLY DEBILITATING MENTAL DISORDER AFFECTING UP TO 15% OF THE POPULATION AT LEAST ONCE IN THEIR LIFETIME, WITH HUGE COSTS FOR SOCIETY. NEUROBIOLOGICAL MECHANISMS OF DEPRESSION ARE STILL NOT WELL KNOWN, ALTHOUGH THERE IS CONSENSUS ABOUT INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. ANTIDEPRESSANT MEDICATIONS ARE FREQUENTLY USED IN DEPRESSION, BUT AT LEAST 50% OF PATIENTS ARE POOR RESPONDERS, EVEN TO MORE RECENTLY DISCOVERED MEDICATIONS. FURTHERMORE, CLINICAL RESPONSE ONLY OCCURS FOLLOWING WEEKS TO MONTHS OF TREATMENT AND ONLY CHRONIC TREATMENT IS EFFECTIVE, SUGGESTING THAT ACTIONS BEYOND THE RAPIDLY OCCURRING EFFECT OF ENHANCING MONOAMINERGIC SYSTEMS, SUCH AS ADAPTATION OF THESE SYSTEMS, ARE RESPONSIBLE FOR THE EFFECTS OF ANTIDEPRESSANTS. RECENT STUDIES INDICATE THAT AN IMPAIRMENT OF SYNAPTIC PLASTICITY (NEUROGENESIS, AXON BRANCHING, DENDRITOGENESIS AND SYNAPTOGENESIS) IN SPECIFIC AREAS OF THE CNS, PARTICULARLY THE HIPPOCAMPUS, MAY BE A CORE FACTOR IN THE PATHOPHYSIOLOGY OF DEPRESSION. THE ABNORMAL NEURAL PLASTICITY MAY BE RELATED TO ALTERATIONS IN THE LEVELS OF NEUROTROPHIC FACTORS, NAMELY BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), WHICH PLAY A CENTRAL ROLE IN PLASTICITY. AS BDNF IS REPRESSED BY STRESS, EPIGENETIC REGULATION OF THE BDNF GENE MAY PLAY AN IMPORTANT ROLE IN DEPRESSION. THE HIPPOCAMPUS IS SMALLER IN DEPRESSED PATIENTS, ALTHOUGH IT IS UNCLEAR WHETHER SMALLER SIZE IS A CONSEQUENCE OF DEPRESSION OR A PRE-EXISTING, VULNERABILITY MARKER FOR DEPRESSION. ENVIRONMENTAL STRESSORS TRIGGERING ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS CAUSE THE BRAIN TO BE EXPOSED TO CORTICOSTEROIDS, AFFECTING NEUROBEHAVIOURAL FUNCTIONS WITH A STRONG DOWNREGULATION OF HIPPOCAMPAL NEUROGENESIS, AND ARE A MAJOR RISK FACTOR FOR DEPRESSION. ANTIDEPRESSANT TREATMENT INCREASES BDNF LEVELS, STIMULATES NEUROGENESIS AND REVERSES THE INHIBITORY EFFECTS OF STRESS, BUT THIS EFFECT IS EVIDENT ONLY AFTER 3-4 WEEKS OF ADMINISTRATION, THE TIME COURSE FOR MATURATION OF NEW NEURONS. THE ABLATION OF HIPPOCAMPAL NEUROGENESIS BLOCKS THE BEHAVIOURAL EFFECTS OF ANTIDEPRESSANTS IN ANIMAL MODELS. THE ABOVE FINDINGS SUGGEST NEW POSSIBLE TARGETS FOR THE PHARMACOTHERAPY OF DEPRESSION SUCH AS NEUROTROPHIC FACTORS, THEIR RECEPTORS AND RELATED INTRACELLULAR SIGNALLING CASCADES; AGENTS COUNTERACTING THE EFFECTS OF STRESS ON HIPPOCAMPAL NEUROGENESIS (INCLUDING ANTAGONISTS OF CORTICOSTEROIDS, INFLAMMATORY CYTOKINES AND THEIR RECEPTORS); AND AGENTS FACILITATING THE ACTIVATION OF GENE EXPRESSION AND INCREASING THE TRANSCRIPTION OF NEUROTROPHINS IN THE BRAIN. 2011 16 1790 29 EFFECT OF CHRONIC MILD STRESS ON HIPPOCAMPAL TRANSCRIPTOME IN MICE SELECTED FOR HIGH AND LOW STRESS-INDUCED ANALGESIA AND DISPLAYING DIFFERENT EMOTIONAL BEHAVIORS. THERE IS INCREASING EVIDENCE THAT MOOD DISORDERS MAY DERIVE FROM THE IMPACT OF ENVIRONMENTAL PRESSURE ON GENETICALLY SUSCEPTIBLE INDIVIDUALS. STRESS-INDUCED HIPPOCAMPAL PLASTICITY HAS BEEN IMPLICATED IN DEPRESSION. WE STUDIED HIPPOCAMPAL TRANSCRIPTOMES IN STRAINS OF MICE THAT DISPLAY HIGH (HA) AND LOW (LA) SWIM STRESS-INDUCED ANALGESIA AND THAT DIFFER IN EMOTIONAL BEHAVIORS AND RESPONSES TO DIFFERENT CLASSES OF ANTIDEPRESSANTS. CHRONIC MILD STRESS (CMS) AFFECTED EXPRESSION OF A NUMBER OF GENES COMMON FOR BOTH STRAINS. CMS ALSO PRODUCED STRAIN SPECIFIC CHANGES IN EXPRESSION SUGGESTING THAT HIPPOCAMPAL RESPONSES TO STRESS DEPEND ON GENOTYPE. CONSIDERABLY LARGER NUMBER OF GENES, BIOLOGICAL PROCESSES, MOLECULAR FUNCTIONS, BIOCHEMICAL PATHWAYS, AND GENE NETWORKS WERE AFFECTED BY CMS IN LA THAN IN HA MICE. THE RESULTS SUGGEST THAT POTENTIAL DRUG TARGETS AGAINST DETRIMENTAL EFFECTS OF STRESS INCLUDE GLUTAMATE TRANSPORTERS, AND CHOLINERGIC, CHOLECYSTOKININ (CCK), GLUCOCORTICOIDS, AND THYROID HORMONES RECEPTORS. FURTHERMORE, SOME BIOLOGICAL PROCESSES EVOKED BY STRESS AND DIFFERENT BETWEEN THE STRAINS, SUCH AS APOPTOSIS, NEUROGENESIS AND CHROMATIN MODIFICATIONS, MAY BE RESPONSIBLE FOR THE LONG-TERM, IRREVERSIBLE EFFECTS OF STRESS AND SUGGEST A ROLE FOR EPIGENETIC REGULATION OF MOOD RELATED STRESS RESPONSES. 2011 17 3587 34 IMPACT OF TLR4 ON BEHAVIORAL AND COGNITIVE DYSFUNCTIONS ASSOCIATED WITH ALCOHOL-INDUCED NEUROINFLAMMATORY DAMAGE. TOLL-LIKE RECEPTORS (TLRS) PLAY AN IMPORTANT ROLE IN THE INNATE IMMUNE RESPONSE, AND EMERGING EVIDENCE INDICATES THEIR ROLE IN BRAIN INJURY AND NEURODEGENERATION. OUR RECENT RESULTS HAVE DEMONSTRATED THAT ETHANOL IS CAPABLE OF ACTIVATING GLIAL TLR4 RECEPTORS AND THAT THE ELIMINATION OF THESE RECEPTORS IN MICE PROTECTS AGAINST ETHANOL-INDUCED GLIAL ACTIVATION, INDUCTION OF INFLAMMATORY MEDIATORS AND APOPTOSIS. THIS STUDY WAS DESIGNED TO ASSESS WHETHER ETHANOL-INDUCED INFLAMMATORY DAMAGE CAUSES BEHAVIORAL AND COGNITIVE CONSEQUENCES, AND IF BEHAVIORAL ALTERATIONS ARE DEPENDENT OF TLR4 FUNCTIONS. HERE WE SHOW IN MICE DRINKING ALCOHOL FOR 5MONTHS, FOLLOWED BY A 15-DAY WITHDRAWAL PERIOD, THAT ACTIVATION OF THE ASTROGLIAL AND MICROGLIAL CELLS IN FRONTAL CORTEX AND STRIATUM IS MAINTAINED AND THAT THESE EVENTS ARE ASSOCIATED WITH COGNITIVE AND ANXIETY-RELATED BEHAVIORAL IMPAIRMENTS IN WILD-TYPE (WT) MICE, AS DEMONSTRATED BY TESTING THE ANIMALS WITH OBJECT MEMORY RECOGNITION, CONDITIONED TASTE AVERSION AND DARK AND LIGHT BOX ANXIETY TASKS. MICE LACKING TLR4 RECEPTORS ARE PROTECTED AGAINST ETHANOL-INDUCED INFLAMMATORY DAMAGE, AND BEHAVIORAL ASSOCIATED EFFECTS. WE FURTHER ASSESS THE POSSIBILITY OF THE EPIGENETIC MODIFICATIONS PARTICIPATING IN SHORT- OR LONG-TERM BEHAVIORAL EFFECTS ASSOCIATED WITH NEUROINFLAMMATORY DAMAGE. WE SHOW THAT CHRONIC ALCOHOL TREATMENT DECREASES H4 HISTONE ACETYLATION AND HISTONE ACETYLTRANSFERASES ACTIVITY IN FRONTAL CORTEX, STRIATUM AND HIPPOCAMPUS OF WT MICE. ALTERATIONS IN CHROMATIN STRUCTURE WERE NOT OBSERVED IN TLR4(-/-) MICE. THESE RESULTS PROVIDE THE FIRST EVIDENCE OF THE ROLE THAT TLR4 FUNCTIONS PLAY IN THE BEHAVIORAL CONSEQUENCES OF ALCOHOL-INDUCED INFLAMMATORY DAMAGE AND SUGGEST THAT THE EPIGENETIC MODIFICATIONS MEDIATED BY TLR4 COULD CONTRIBUTE TO SHORT- OR LONG-TERM ALCOHOL-INDUCED BEHAVIORAL OR COGNITIVE DYSFUNCTIONS. 2011 18 5207 28 PRENATAL STRESS INDUCES SPATIAL MEMORY DEFICITS AND EPIGENETIC CHANGES IN THE HIPPOCAMPUS INDICATIVE OF HETEROCHROMATIN FORMATION AND REDUCED GENE EXPRESSION. STRESS DURING PREGNANCY HAS A WIDE VARIETY OF NEGATIVE EFFECTS IN BOTH HUMAN [1] AND ANIMAL OFFSPRING [2]. THESE EFFECTS ARE ESPECIALLY APPARENT IN VARIOUS FORMS OF LEARNING AND MEMORY SUCH AS OBJECT RECOGNITION [3] AND SPATIAL MEMORY [4]. THE COGNITIVE EFFECTS OF PRENATAL STRESS (PNS) MAY BE MEDIATED THROUGH EPIGENETIC CHANGES SUCH AS HISTONE ACETYLATION AND DNA METHYLATION [5]. AS SUCH, THE PRESENT STUDY INVESTIGATED THE EFFECTS OF CHRONIC UNPREDICTABLE PNS ON MEMORY AND EPIGENETIC MEASURES IN ADULT OFFSPRING. MICE THAT UNDERWENT PNS EXHIBITED IMPAIRED SPATIAL MEMORY IN THE MORRIS WATER MAZE, AS WELL AS SEX-SPECIFIC CHANGES IN LEVELS OF DNA METHYLTRANSFERASE (DNMT) 1 PROTEIN, AND ACETYLATED HISTONE H3 (ACH3) IN THE HIPPOCAMPUS, AND SERUM CORTICOSTERONE. MALE MICE EXPOSED TO PNS EXHIBITED DECREASED HIPPOCAMPAL ACH3, WHEREAS FEMALE PNS MICE DISPLAYED A FURTHER REDUCTION IN ACH3, AS WELL AS HEIGHTENED HIPPOCAMPAL DNMT1 PROTEIN LEVELS AND CORTICOSTERONE LEVELS. THESE DATA SUGGEST THAT PNS MAY EPIGENETICALLY REDUCE TRANSCRIPTION IN THE HIPPOCAMPUS, PARTICULARLY IN FEMALES IN WHOM THIS EFFECT MAY BE RELATED TO INCREASED BASELINE STRESS HORMONE LEVELS, AND WHICH MAY UNDERLIE THE SEXUAL DIMORPHISM IN RATES OF MENTAL ILLNESS IN HUMANS. 2015 19 3973 31 LONG-TERM BEHAVIORAL AND NEUROENDOCRINE ALTERATIONS FOLLOWING CHRONIC SOCIAL STRESS IN MICE: IMPLICATIONS FOR STRESS-RELATED DISORDERS. THE PERIOD OF ADOLESCENCE IS CHARACTERIZED BY A HIGH VULNERABILITY TO STRESS AND TRAUMA, WHICH MIGHT RESULT IN LONG-LASTING CONSEQUENCES AND AN INCREASED RISK TO DEVELOP PSYCHIATRIC DISORDERS. USING A RECENTLY DEVELOPED MOUSE MODEL FOR CHRONIC SOCIAL STRESS DURING ADOLESCENCE, WE STUDIED PERSISTENT NEUROENDOCRINE AND BEHAVIORAL EFFECTS OF CHRONIC SOCIAL STRESS OBTAINED 12 MONTHS AFTER CESSATION OF THE STRESSOR. AS A REFERENCE, WE INVESTIGATED IMMEDIATE EFFECTS OF CHRONIC STRESS EXPOSURE OBTAINED AT THE END OF THE CHRONIC STRESS PERIOD. IMMEDIATELY AFTER THE 7 WEEK CHRONIC STRESS PERIOD STRESSED ANIMALS SHOW SIGNIFICANTLY INCREASED ADRENAL WEIGHTS, DECREASED THYMUS WEIGHT, INCREASED BASAL CORTICOSTERONE SECRETION AND A FLATTENED CIRCADIAN RHYTHM. FURTHERMORE, STRESSED ANIMALS DISPLAY AN INCREASED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE AND THE NOVELTY-INDUCED SUPPRESSION OF FEEDING TEST. HIPPOCAMPAL MINERALOCORTICOID RECEPTOR (MR) AND THE GLUCOCORTICOID RECEPTOR (GR) MRNA LEVELS WERE SIGNIFICANTLY DECREASED. TO INVESTIGATE PERSISTENT CONSEQUENCES OF THIS EARLY STRESSFUL EXPERIENCE, THE SAME PARAMETERS WERE ASSESSED IN AGED MICE 12 MONTHS AFTER THE CESSATION OF THE STRESSOR. INTERESTINGLY, WE STILL FOUND DIFFERENCES BETWEEN FORMERLY STRESSED AND CONTROL MICE IN IMPORTANT STRESS-RELATED PARAMETERS. MR EXPRESSION LEVELS WERE SIGNIFICANTLY LOWER IN STRESSED ANIMALS, SUGGESTING LASTING, POSSIBLY EPIGENETIC ALTERATIONS IN GENE EXPRESSION REGULATION. FURTHERMORE, WE OBSERVED LONG-TERM BEHAVIORAL ALTERATIONS IN ANIMALS STRESSED DURING ADOLESCENCE. THUS, WE COULD DEMONSTRATE THAT CHRONIC STRESS EXPOSURE DURING A CRUCIAL DEVELOPMENTAL TIME PERIOD RESULTS IN LONG-TERM, PERSISTENT EFFECTS ON PHYSIOLOGICAL AND BEHAVIORAL PARAMETERS THROUGHOUT LIFE, WHICH MAY CONTRIBUTE TO AN ENHANCED VULNERABILITY TO STRESS-INDUCED DISEASES. 2008 20 948 30 CHRONIC METABOLIC DERANGEMENT-INDUCED COGNITIVE DEFICITS AND NEUROTOXICITY ARE ASSOCIATED WITH REST INACTIVATION. CHRONIC METABOLIC ALTERATIONS MAY REPRESENT A RISK FACTOR FOR THE DEVELOPMENT OF COGNITIVE IMPAIRMENT, DEMENTIA, OR NEURODEGENERATIVE DISEASES. HYPERGLYCEMIA AND OBESITY ARE KNOWN TO IMPRINT EPIGENETIC MARKERS THAT COMPROMISE THE PROPER EXPRESSION OF CELL SURVIVAL GENES. HERE, WE SHOWED THAT CHRONIC HYPERGLYCEMIA (60 DAYS) INDUCED BY A SINGLE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN COMPROMISED COGNITION BY REDUCING HIPPOCAMPAL ERK SIGNALING AND BY INDUCING NEUROTOXICITY IN RATS. THE MECHANISMS APPEAR TO BE LINKED TO REDUCED ACTIVE DNA DEMETHYLATION AND DIMINISHED EXPRESSION OF THE NEUROPROTECTIVE TRANSCRIPTION FACTOR REST. THE IMPACT OF THE RELATIONSHIP BETWEEN ADIPOSITY AND DNA HYPERMETHYLATION ON REST EXPRESSION WAS ALSO DEMONSTRATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN OBESE CHILDREN WITH REDUCED LEVELS OF BLOOD ASCORBATE. THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS AND THE COGNITIVE IMPAIRMENT REPORTED IN OBESE CHILDREN, ADOLESCENTS, AND ADULTS SUGGEST THAT THE CORRECTION OF THE ANTHROPOMETRY AND THE PERIPHERAL METABOLIC ALTERATIONS WOULD PROTECT BRAIN HOMEOSTASIS AND REDUCE THE RISK OF DEVELOPING NEURODEGENERATIVE DISEASES. 2019